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Biomedical subjects

H Wilke

Publications and source records attributed to H Wilke.

At least 55 records · Page 3Linked to original sources
PubMed1997

Phase II trial of continuous oral trofosfamide in patients with advanced colorectal cancer refractory to 5-fluorouracil.

Fourteen patients with 5-fluorouracil (5-FU) refractory, progressive colorectal cancer metastatic to liver and/or lung were treated with continuous oral trofosfamide, an alkylating agent structurally related to cyclophosphamide and ifosfamide. Trofosfamide was given daily at 200 mg/day. No objective partial or complete responses were seen in 14 evaluable patients. There were four patients with stable disease or minor responses; the median duration of stable disease during trofosfamide treatment was 14 weeks, with of range of 12-36 weeks. Mild to moderate side effects were reported in seven patients including grade 1-2 nausea in four patients, grade 1 leukopenia in two patients and grade 1 anemia in one patient. Trofosfamide in this dose and schedule shows minor activity in 5-FU refractory colorectal cancer. Because of very little side effects, dose escalations appear to be possible.

Adult↗
PubMed1997

Drug interactions of 5-fluorouracil with either cisplatin or lobaplatin--a new, clinically active platinum analog in established human cancer cell lines.

Lobaplatin [1,2-diaminomethylcyclobutane platinum(II)-lactate] is a new platinum compound which appears to possess incomplete cross-resistance to cisplatin and might have a favorable pattern of side effects. Since lobaplatin has activity in esophageal cancer, combination protocols with 5-fluorouracil (5-FU) are evaluated. In order to assess the mode of action of lobaplatin when combined with 5-FU, two human cancer cell lines were treated with various combinations of 5-FU given for either 2 or 24h and lobaplatin. Drug interactions were evaluated by isobologram analysis. Lobaplatin showed basically the same interaction pattern when combined with 5-FU as cisplatin. The combination of either platinum analog with a 24 h exposure to 5-FU was superior to a short-term 5-FU exposure. Furthermore, when 5-FU was given for 24 h, no additional effect of folinic acid was seen. From these data we conclude that cisplatin and lobaplatin show similar interactions with 5-FU. Protracted infusion schedules of 5-FU appear to be more active than bolus application.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

An international, multidisciplinary approach to the management of advanced colorectal cancer. International Working Group in Colorectal Cancer.

The International Working Group in Colorectal Cancer conducted a survey (the Colorectal Cancer Care Pathway Review) in the summer of 1995 to examine medical, surgical and oncology nursing perceptions of patient management throughout Europe and the United States. The sample included 319 oncologists (surgical, medical and radiation) and 103 oncology nurses from a variety of centres in France, Germany, Italy, the United Kingdom and the United States. In response to issues identified in the Colorectal Cancer Care Pathway Review, a model for the optimal management of patients has been developed by the Working Group. The objectives of the Patient Management Model are: to define current best practice in advanced colorectal cancer; and to identify areas for ongoing research and clinical trials. Due to the multicultural nature of the Working Group, the model incorporates the differences in treatment that occur between countries. The Patient Management Model gives recommendations on treatment issues such as diagnosis, staging of disease, management strategy and therapy considerations including surgery, radiotherapy, chemotherapy, palliative supportive care, therapy management, auxiliary management and patient support. A multidisciplinary team approach to patient management is recommended to ensure optimal treatment and care. The multidisciplinary team should include all those involved in the treatment of the patient including specialists such as the oncology nurse. A summary of the recommendations of the Patient Management Model is presented here.

Colorectal Neoplasms↗
PubMed1997

Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors.

PURPOSE AND METHODS: Although fluoropyrimidines, in particular, fluorouracil (5-FU) and fluorodeoxyuridine (FdUrd), are active alone and in combination with other agents in a variety of human malignancies, therapeutic selectivity, resistance, and efficacy have been a major limitation in cancer therapy. Preclinical and clinical results in advanced and adjuvant colorectal cancers confirmed that the therapeutic efficacy of fluoropyrimidines, with thymidylate synthase (TS) as a primary target, can be improved significantly with leucovorin (LV) modulation. With the recognition that TS is an important therapeutic target, direct and specific inhibitors have been developed and are under intensive preclinical and clinical evaluation, primarily in patients with colorectal cancer, with demonstrable activity. The direct TS inhibitors have been shown to be potent, with a high level of specificity under therapeutic conditions for TS. This includes ZD1694, AG337, and LY231514. To date, although the therapeutic activity of both direct and indirect inhibitors of TS is similar, differences in the magnitude and profile of toxicity have been observed. A phase III comparative evaluation of a direct inhibitor of TS (ZD1694) with an indirect inhibitor (5-FU/LV) has been completed and showed similar activity but reduced toxicity in favor of ZD1694. RESULTS: Recognition that greater than 95% of the injected dose of 5-FU is rapidly inactivated by dihydropyrimidine dehydrogenase (DPD) to therapeutically inactive products, but with toxicity to normal tissues, led to the development of inhibitors of this enzyme with the aim to modify the therapeutic index of 5-FU. Several inhibitors in combination with 5-FU are under preclinical and clinical evaluation, including uracil and 5-chloro-2,4-dihydroxy pyridine, as modulators of 5-FU derived from its prodrug tegafur and 5-ethynyluracil as a modulator of 5-FU. CONCLUSION: In this review, an update of the present status of direct and indirect inhibitors of TS is discussed, as well as the future prospect for new drugs alone and in combination.

Antimetabolites, Antineoplastic↗
PubMed1997

Infusional 5-FU, folinic acid, paclitaxel, and cisplatin for metastatic breast cancer.

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil(5-FU)/folinic acid (HD5-FU/FA) in intensively pretreated patients with metastatic breast cancer prompted addition of paclitaxel (Taxol) to the regimen, for a phase I/II study of outpatient second-line treatment of metastatic breast cancer. That study further prompted the addition of cisplatin (Platinol) to the regimen for first-line treatment. So far, 28 patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, but no prior chemotherapy for metastatic disease. Patients were treated with HD5-FU 2 g/m2 (24-hour infusion) plus FA 500 mg/m2 (2-hour infusion prior to FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition, paclitaxel 175 mg/m2 (3-hour infusion) was administered on days 0 and 21 and cisplatin 50 mg/m2 (1-hour infusion) on days 1 and 22 prior to HD5-FU/FA, repeated every 50 days. Patients were treated as outpatients using Port-a-Cath systems and portable pumps. Neutropenia was common (67% World Health Organization grade 3) but mild to moderate in most patients and was of short duration. No hospitalizations were required because of febrile neutropenia, and no granulocyte colony-stimulating factor support was used. Aside from common total alopecia, nonhematologic toxicities consisted mainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting. Hand-foot syndrome and peripheral neuropathy were cumulative and occurred most commonly during the third treatment cycle, with mild-to-moderate expression. In 28 patients with bidimensionally measurable disease, 25% (7/28) attained a complete response, 57% (16/28) achieved partial response, 11% (3/28) had stable disease, and 7% (2/28) had disease progression. Overall response was 82% (95% confidence interval, 66% to 100%). Eight of 28 patients are still receiving treatment. It is concluded that the combination of paclitaxel/cisplatin with weekly HD5-FU/FA appears to be effective in the first-line treatment of metastatic breast cancer. Preliminary results must be confirmed by the final analysis of response duration, time to progression, and survival.

Adult↗
PubMed1997

Infusional 5-fluorouracil/leucovorin plus paclitaxel and cisplatin in the first-line treatment of metastatic breast cancer: results of a phase II study.

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose, 24-hour infusional 5-fluorouracil (5-FU)/leucovorin (LV) in intensively pretreated patients with metastatic breast cancer prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to the regimen for a phase I/II study of outpatient second-line treatment of metastatic breast cancer. That study further prompted the addition of cisplatin to the regimen for first-line treatment. Twenty-eight patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant chemotherapy in 24 of 28 patients, but no prior chemotherapy for metastatic disease. Patients were treated with high-dose 5-FU 2 g/m2 (24-hour infusion) plus LV 500 mg/m2 (2-hour infusion before 5-FU) weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36); in addition, paclitaxel 175 mg/m2 (3-hour infusion) was administered on days 0 and 21 and cisplatin 50 mg/m2 (1-hour infusion) on days 1 and 22 before high-dose 5-FU/LV, repeated every 50 days. Patients were treated as outpatients using Port-a-Cath systems (SIMS Deltec Inc, St Paul, MN) and portable pumps. Neutropenia was common but mild to moderate and of short duration in most patients. No hospitalizations were required because of febrile neutropenia, and no granulocyte colony-stimulating factor support was used. Aside from common total alopecia, nonhematologic toxicities consisted mainly of moderate myalgia, diarrhea, mucositis, and nausea and vomiting. Hand-foot syndrome and peripheral neuropathy were cumulative and occurred most commonly during the third treatment cycle with mild to moderate expression. In 28 patients with bidimensionally measurable disease, 25% (seven of 28) attained a complete response, 57% (16 of 28) achieved a partial response, 11% (three of 28) had stable disease, and 7% (two of 28) had disease progression. Overall response was 82% (95% confidence interval, 66% to 100%). We conclude that the combination of paclitaxel/cisplatin with weekly high-dose infusional 5-FU/LV appears to be effective in the first-line treatment of metastatic breast cancer. Preliminary results must be confirmed by the final analysis of response duration, time to progression, and survival.

Adult↗
PubMed1996

[Leiomyosarcoma of the stomach--clinical aspects, morphology and therapy].

BACKGROUND: Due to the rarity of gastric leiomyosarcomas, only little is known on the results of diagnostics and therapy of these tumors. According to literature, the problem of suitable criteria in determining malignancy of these neoplasms is unsettled. PATIENTS AND METHOD: 21 patients (10 male, 11 female; aged 13 to 74 [53 +/- 13,9] years) with leiomyosarcomas of the stomach were treated from 1978 to 1993. In a retrospective study, the diagnostic and therapeutic results and the pathologic features of these patients are compared with the results of literature. RESULTS: Diagnosis was rarely confined preoperatively. Potentially curative resection was possible in 13/21 cases. Five year survival was 44% overall (R0-resections: 60%, R1/2-resections 22%) with a wide spread of individual cases. Pathologic examination of the tumors showed only half of the tumors classifiable according to the system of McGrath. Some well differentiated tumors revealed unclear malignancy criteria. Analysis of prognostic factors showed no statistically significant influence of surgical radicality but a significant influence of tumor size, mitotic activity and nuclear grading on survival and recurrence. CONCLUSIONS: Because of their rare incidence, the treatment of gastric leiomyosarcomas remains non-standardized. Surgical radical removal of the tumor seems to promise the largest benefit. The treatment of patients with residual or recurrent tumors remains individual, no adjuvant radio- or chemotherapeutical treatment can be generally recommended.

Adolescent↗
PubMed1996

Preoperative chemotherapy in gastric cancer.

Even with extended surgery, including systematic lymphadenectomy of the lymph node compartment II, only half of the patients with locally advanced gastric cancer (LAGC)-which comprises stages IIIA, IIIB, and IV-undergo macroscopic and microscopic tumor-free resection (i.e., R0 resection, according to UICC 1987/AICC 1988). An improvement in this situation is best accomplished by preoperative treatment modalities to increase the R0 resection rate and by preoperative and postoperative treatment to reduce local recurrences and distant metastases. For LAGC, which includes approximately two thirds of patients with locoregionally confined tumors, preoperative chemotherapy (CTx) represents a promising approach. Among a group of patients with surgically or clinically staged unresectable LAGC, approximately half underwent R0 resection after downstaging induced by active CTx. The long-term survival of these patients seems to be improved. Even in patients who had primarily unresectable tumors as defined by explorative laparotomy, the long-term survival was about 20% after preoperative CTx and subsequent surgery. Based on these experiences, randomized trials investigating preoperative CTx versus surgery alone are clearly needed to define whether such an approach has an impact on RO resection rates and survival of patients with LAGC. Preconditions for such trials are clinical staging procedures, including endoscopic ultrasonography (T category) and surgical laparoscopy plus lavage (excluding peritoneal carcinomatosis), and a standardized surgical procedure.

Combined Modality Therapy↗
PubMed1996

Phase I study with a weekly 1 h infusion of paclitaxel in heavily pretreated patients with metastatic breast and ovarian cancer.

Paclitaxel has proven to be an active agent in the treatment of breast and ovarian cancer [Seidman AD, Ann Oncol 1994, 5 (Suppl. 6), 17-22], but the optimal dose and schedule remain undefined. We performed a phase I study with a weekly 1 h infusion of paclitaxel. After premedication, patients received a 1 h infusion of paclitaxel on days 1, 8, 15, 22, 29 and 36 (every 50 days) using the following dose levels: dose level 1 70 mg/m2, dose level 2 80 mg/m2, dose level 90 mg/m2, dose level 4 100 mg/m2, 20 patients (17 breast, 3 ovarian cancer) with anthracycline- or platinum-refractory disease entered this trial. No dose limiting toxicities occurred at dose levels 1-3. 2 of the 4 patients at dose level 4 had neutropenia WHO grade 4. At all dose levels responses could be observed. Maximal tolerable dose (MTD) was reached using dose level 4. Paclitaxel, given in a weekly 1 h infusion, is safe and shows mild toxicity in heavily pretreated breast and ovarian cancer patients. We recommend dose level 3 for phase II studies.

Adult↗
PubMed1996

Activity- and schedule-dependent interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide in cisplatin-sensitive and -refractory human ovarian carcinoma cell lines.

Paclitaxel has demonstrated broad clinical activity in a variety of malignancies both alone and in combination with other chemotherapeutic agents. The in vitro cytotoxicity of a 2 h exposure to paclitaxel, hydroperoxy-ifosfamide and etoposide alone, in combination and in sequence, was evaluated against established cisplatin-sensitive and cisplatin-refractory human ovarian carcinoma cell lines using isobologram analysis. The combinations of either paclitaxel-hydroperoxy-ifosfamide or paclitaxel-etoposide were found to be additive or synergistic when the drugs were given simultaneously or when paclitaxel was given 24 h before hydroperoxy-ifosfamide or etoposide respectively. However, when etoposide or hydroperoxy-ifosfamide were given before paclitaxel, antagonistic interactions were observed. With regard to etoposide this antagonism was evident for up to 24 h. In agreement with our data with the schedule-dependent interactions of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines, these data demonstrate that the interactions of paclitaxel, etoposide and hydroperoxy-ifosfamide are also highly schedule dependent and applications of etoposide or ifosfamide before paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Phase I/II study with a weekly 24-hour infusion of 5-fluorouracil plus high-dose folinic acid (HD-FU/FA) in intensively pretreated patients with metastatic breast cancer.

BACKGROUND: In metastatic breast cancer patients who have had prior exposure to anthracyclines, single agents induce less than 15% and combination chemotherapy less than 20%-30% of objective responses. Therefore more active and tolerable salvage regimens are needed. PATIENTS AND METHODS: Forty-three patients with advanced breast cancer pretreated with 1-5 (median 2) different chemotherapy regimens were entered into this phase I/II trial. Treatment consisted of folinic acid (FA) (500 mg/m2, i.v., 2-hour infusion) followed by a 24-hour infusion of 5-fluorouracil (FU) which was escalated from 1.5 g/m2 (dose level (dl 1)), to 1.8 g/m2 (dl 2) to 2.1 g/m2 (dl 3). Therapy was given as outpatient treatment once weekly times 6 followed by a 2-week rest. RESULTS: HD-FU/FA was well tolerated. No dose-limiting toxicity occurred at dl 1 or 2. Only 3/32 (9%) patients had WHO grade 3/4 toxicities (gastrointestinal toxicities, hand-foot-syndrome) at dl 3. The response rate for all 32 of the patients treated at dl 3 was 41% (13/32). In the 24 patients with anthracycline-refractory disease, a response rate of 41% (10/24) was achieved. The median remission duration was 11 months and the median survival time 19 months. CONCLUSIONS: This schedule of FU/FA is a safe outpatient treatment with substantial activity in intensively pretreated breast cancer patients.

Adult↗
PubMed1996

Combined preoperative chemotherapy and radiotherapy in patients with locally advanced esophageal cancer. Interim analysis of a phase II trial.

PURPOSE: The prognosis of patients with locally advanced esophageal cancer (LAEC) remains poor when treated with local modalities. An intensive preoperative program with chemoradiotherapy was used to evaluate the curative resection rate, pathologic response, and survival of patients with LAEC. PATIENTS AND METHODS: Ninety patients with LAEC were treated preoperatively with chemotherapy (three courses of fluorouracil, leucovorin, etoposide, and cisplatin [FLEP]) followed by concurrent chemoradiotherapy (one course of cisplatin plus etoposide in combination with 40 Gy of radiation). Transthoracic esophagectomy was performed 4 weeks after the end of radiation. RESULTS: Seventy-two patients were included in this evaluation. Forty-four (61%) underwent a complete tumor resection, and 16 (22%) had no tumor in the resected specimen (pathologic complete response [PCR]). The operative mortality rate was 15%. At a median follow-up time of 22 months (range, 12 to 41), the median survival duration of all 72 patients was 17 months (range, 1 to 41+). The calculated survival rates at 3 years were 33%, 42%, and 68% for all patients, patients after complete resection, and patients with PCR, respectively. CONCLUSION: This combined treatment modality is active in LAEC, with a PCR in 33% of the patients undergoing surgery. The results appear improved compared with those reported with surgery alone, by approximately doubling the 3-year survival rate. The high efficacy of preoperative chemoradiation warrants evaluation of the role of surgery in LAEC.

Adenocarcinoma↗
PubMed1996

Preclinical and clinical study results of the combination of paclitaxel and 5-fluorouracil/folinic acid in the treatment of metastatic breast cancer.

Results of phase II studies have demonstrated high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (5-FU/FA) when given to intensively pretreated patients with metastatic breast cancer. In a phase I/II study of outpatients, we have added paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in an attempt to improve the results. Patients were treated weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36) with high-dose 5-FU 2.0 g/m2 by 24-hour infusion with FA 500 mg/m2 given as a 2-hour infusion prior to 5-FU. Paclitaxel 175 mg/m2 by 3-hour infusion was administered on days 1 and 22 prior to 5-FU/FA. Each cycle comprised 6 weeks followed by 2 weeks rest; the number of cycles depended on response and toxicity. To date, 40 patients have been entered into this trial during phase II. Pretreatment included adjuvant chemotherapy among 12 patients, prior chemotherapy for metastasis in nine patients, and both adjuvant therapy and treatment for metastasis in 19 patients. Of 24 anthracycline-pretreated patients, 20 had anthracycline-resistant disease. The observed toxicities were of mild to moderate intensity, especially with regard to myelosuppression. Thirty-four patients have been evaluable for response. Response rates included 3% complete response (one of 34 patients) and 50% partial response (17 of 34 patients) for an overall response rate of 53% (95% confidence interval, 37% to 69%). Additionally, 41% (14 of 34 patients) had stable disease and 6% had progressive disease (two of 34 patients). Among 20 anthracycline-resistant patients, 55% responded (11 of 20 patients). The median number of treatment cycles per patient was three (range, one to five); time to maximum response, 2 months (range, 1 to 5 months); and remission duration, 9 months (range, 2 to 17 months). Median time to progression was 10 months (range, 3 to 17 months). In conclusion, the combination of paclitaxel with weekly high-dose 5-FU/FA is well tolerated as second-line treatment of metastatic breast cancer, with high activity, even in patients with anthracycline-resistant disease. The regimen can be administered safely on an outpatient basis.

Adult↗
PubMed1996

Paclitaxel combined with weekly high-dose 5-fluorouracil/folinic acid and cisplatin in the treatment of advanced breast cancer.

Our phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil (5-FU)/folinic acid (FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/ II outpatient study. Patients were treated with high-dose 5-FU (by 24-hour infusion) and FA (by 2-hour infusion prior to 5-FU) weekly for 6 weeks (day 1, 8, 15, 22, 29, and 36) repeated every 50 days; in addition, paclitaxel was administered by 3-hour infusion on days 1 and 22. The following dose levels were used in phase 1 of the study. In dose levels 1 through 4, FA was given at a fixed dose of 500 mg/m2, followed by escalating doses of high-dose 5-FU (24-hour infusions of 1.5 [dose level 1], 1.8 [dose level 2], and 2.0 g/m2 [dose levels 3 and 4]). The paclitaxel dose, given over 3 hours on days 1 and 22, was 135 mg/m2 for dose levels 1 through 3 and 175 mg/m2 at dose level 4. Dose level 4 was chosen for further evaluation in the phase II portion of the trial. Among the 46 patients who entered this part of the trial, the median age was 46 years (age range, 26 to 70 years), the World Health Organization performance status was 0 to 1, and the median number of metastatic sites was 2.5 (range, one to four). All patients had bidimensionally measurable disease. Nine patients previously had received adjuvant chemotherapy, 16 had received prior chemotherapy for metastasis, and 21 had been treated with both types of chemotherapy. Of 29 anthracycline-pretreated patients, 25 had anthracycline-resistant disease. Interim results in 35 evaluable patients show complete remission in one patient (3%), partial remissions in 18 (51%), stable disease in 14 (40%), and progressive disease in two (6%). The overall response rate was 54% (95% confidence interval, 36% to 76%). The median number of treatment cycles administered per patient was three (range, one to five), the median time to maximum response was 2 months (range, 1 to 5 months), and the median remission duration was 8+ months (range, 2 to 17 months). Median survival time has not yet been reached. The combination of paclitaxel with weekly high-dose 5-FU/FA was well tolerated in second-line treatment of metastatic breast cancer and results also indicate high efficacy against anthracycline-resistant disease. In an ongoing phase II study we are evaluating the addition of cisplatin to the regimen as first-line treatment of metastatic breast cancer.

Adult↗
PubMed1996

[Adjuvant and neoadjuvant methods: what is their value--do they change surgical procedure?].

Despite advances in surgical treatment for gastrointestinal tumors, in general, improvements in prognosis could not be achieved; therefore other therapeutical options were evaluated in a multimodal concept. Stage III or II/III disease of colorectal cancer appears to benefit from adjuvant chemo/radiotherapy by reduced relapse and mortality rates. After application of preoperative therapy for locally advanced tumors of the upper gastrointestinal tract and rectum tumor debulking and better local tumor control was achieved resulting in an increased curative resection and survival rate. Surgical procedures and the extent of resection should not be modified in multimodal treatment: the aim must be a complete tumor (R0)-resection.

Chemotherapy, Adjuvant↗